dihydroergotoxine and Hypoxia

Utilizing quantitative EEG and psychometric methods we investigated in two subsequent double-blind, placebo-controlled trials the following questions: 1) Does co-dergocrine mesylate (CDM) protect against cerebral hypoxic hypoxidosis as objectivated by neurophysiological and behavioral measures in man? 2) Does CDM offer protection equally both against moderate and marked hypoxia induced experimentally by inhalation of a gas mixture of 9.8% and 8.6% O2 (equivalent to 6000 m and 7000 m altitude, respectively)? 3) Are brain-protective effects of CDM improving by drug administration over a longer period of time (2 weeks)? In the first study, hypoxic hypoxidosis was induced by a fixed gas combination of 9.8% oxygen and 90.2% N2 (equivalent to 6000 m altitude), which was inhaled for 23 min under normobaric conditions by 15 healthy volunteers. They received randomized after an adaptation session placebo and 5 mg CDM. Blood gases, quantitative EEG, and psychometric measures were obtained under normoxic (21% O2) and hypoxic (9.8% O2) conditions before as well as 2, 4, 6 and 8 h after oral drug administration. Blood gas analysis demonstrated under hypoxia a drop in PO2 from 91 to 37 mmHg and in PCO2 from 38 to 33 mmHg, while pH increased from 7.41 to 7.47. Computer-assisted spectral analysis of the EEG showed an increase of delta/theta, decrease of alpha, and an increase of superimposed fast beta activity indicative of deterioration in vigilance. The latter was documented at the behavioral level by deterioration of intellectual and mnestic functions, psychomotor activity, performance in a reaction time task, mood, and wakefulness. CDM attenuated significantly this brain dysfunction, as it attenuated delta/theta and increased alpha-adjacent beta activity. Psychometric performance based on all 11 variables deteriorated under hypoxia by 49% after placebo, while after 5 mg CDM only by 26%. However, in a subsequent double-blind placebo-controlled trial in 12 healthy young volunteers, further augmentation of hypoxia induced by inhalation of a gas combination of 8.6% O2 and 91.4% N2 (equivalent to 7000 m altitude) leading to a drop of PO2 and PCO2 to 32 and 32 mmHg, respectively and an increase of pH to 7.46 resulted in a loss of brain protection, even when CDM was given over 2 weeks daily. Our findings suggest that treatment of organic brain syndromes with nootropic/antihypoxidotics should be initiated in an early rather than a late stage.

Topics: Administration, Inhalation; Adult; Behavior; Blood Gas Analysis; Brain; Dihydroergotoxine; Double-Blind Method; Electroencephalography; Female; Humans; Hypoxia; Male; Oxygen; Psychometrics

In a double-blind placebo-controlled study, the effects of tenilsetam, a novel antihypoxidotic/nootropic agent, on spontaneous and event-related activity of the central and autonomous nervous system were studied in 15 elderly subjects of both sexes aged 58-77 years by means of the Viennese Psychophysiological Test-System (VPTS). The VPTS includes a special selection and combination of experimental situations, physiological measurements, behavioral measurements and data analysis. At weekly intervals, the subjects received randomized single oral doses of placebo, 150 mg, 300 mg and 900 mg tenilsetam (TEN) and 5 mg co-dergocrine-mesylate (CDM) as reference drug. Psychophysiological testings were carried out before and 2 h after drug administration. Evaluation of the spontaneous EEG-activity demonstrated no significant drug effects as compared to placebo. In contrast, TEN showed a dose-dependent augmentation of the N1-P2 and N2-P300 amplitudes of the event-related potentials (ERPs) in specific experimental conditions. In reference to placebo, the increase of N2-P300 amplitude after the highest dosage of TEN, as well as after CDM, amounted to approximately 5 microV, which confirms the hypothesis that nootropic drugs may influence the P300 amplitude in the sense of an improved availability of cognitive processing resources. There was no effect on ERP latencies, on mean amplitudes of contingent negative variation and of post-imperative negative variation, on autonomous nervous system, on psychological measurements, nor on reaction time. However, specific improvements were observed in psychomotor measures, such as synchronization accuracy and rhythmicity. These findings highlight the importance of using EEG and ERP measures in different experimental situations in conjunction with behavioral, psychological and autonomous nervous system measures to study nootropic drug effects.

Topics: Aged; Blinking; Dihydroergotoxine; Electroencephalography; Female; Humans; Hypoxia; Male; Middle Aged; Piperazines; Psychomotor Performance; Psychophysiology; Psychotropic Drugs; Thiophenes

The effects of varying degrees of hypoxia on sleep-wake organization were studied in rats prepared for chronic electrophysiological recording. The influence of Piracetam (75, 50, and 500 mg/kg, i.p.) and Hydergine (0.5, 1, and 3 mg/kg, i.p.) on sleep-wake organization in 10.5% oxygen was also investigated. The sleep-wake organization of rats under the effect of 15.5% oxygen content was unchanged, compared to that of normoxic control. More extreme hypoxia (12.6 and 10.5% oxygen) produced dramatic changes in sleep organization without influencing gross behavior. Paradoxical sleep (PS) stages became less frequent and shortened and were totally absent in 10.5% oxygen. Frequent wakings caused disturbed and superficial sleep. Central biochemical mechanisms, peripheral chemoreceptor reflex pathways and, as a consequence, decrease of duration of deep sleep periods, may contribute to the development of hypoxic sleep disturbances. Piracetam alleviated and Hydergine moderately reversed the hypoxic sleep disturbance.

Topics: Animals; Dihydroergotoxine; Disease Models, Animal; Hypoxia; Male; Piracetam; Rats; Sleep Stages; Sleep Wake Disorders

In order to determine the antianoxic potential of evodiamine, its effects were compared to those of vinpocetine (VPT), using a series of animal models of anoxia. In mice, evodiamine was equivalent to VPT in the KCN-induced anoxia model but was greater than VPT in the low-pressure-induced anoxia model. Its effectiveness was increased by combined treatment with physostigmine, suggesting the involvement of a cholinergic mechanism in the antianoxic action of evodiamine.

Topics: Alkaloids; Animals; Anticonvulsants; Atmospheric Pressure; Dihydroergotoxine; Hypoxia; Male; Mice; Pentobarbital; Plant Extracts; Plants, Medicinal; Potassium Cyanide; Quinazolines; Sleep; Vinca Alkaloids

The protective efficacy of pentoxiphylline, piracetam, and dihydroergotoxine against abrupt hypoxia was tested in a model of acute reversible respiratory failure, where repeated apnoeic attacks were induced by inhalation in repeated hypoxic exposures was reduced in control as well as in dihydroergotoxine-treated animals, it was increased after pentoxiphylline, and was not changed after piracetam. Repeated N2 inhalations reduced the duration of apnoea required for the development of mydriasis in all control cats. There were, however, no such reductions of the apnoeic interval in animals of the three groups treated with cerebroprotective drugs. The ratio between the total duration of hypoxia (hypoxic hyperventilation plus apnoea) and the time of recovery of breathing was significantly higher in the pentoxiphylline-treated animals already during the first hypoxic attack after drug application when compared both to the control and the dihydroergotoxine-treated animals. After piracetam the difference was apparent in the last hypoxic attack only. The model of acute reversible respiratory failure with apnoeic episodes induced repeatedly seems to be useful for testing some properties of cerebroprotective drugs during abrupt hypoxia.

Topics: Animals; Brain Ischemia; Cats; Dihydroergotoxine; Disease Models, Animal; Electrocardiography; Hypoxia; Nitrogen; Pentoxifylline; Piracetam; Respiration, Artificial; Respiratory Insufficiency

Effects of indeloxazine hydrochloride [(+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054] on anoxia were examined. Indeloxazine significantly prolonged survival time of mice subjected to anoxia and improved anoxia-induced impairment of the passive and active avoidance learnings in rats. Indeloxazine at doses inducing anti-anoxic actions showed no effect on cerebral blood flow in cats and pentobarbital sleeping time in mice. Therefore, anti-anoxic actions of indeloxazine are not attributable to cerebral vasodilative or central depressant activities. Calcium hopantenate (cerebral metabolic enhancer) also showed anti-anoxic actions, whereas neither viloxazine, amitriptyline (antidepressant) nor dihydroergotoxine (cerebral vasodilator) showed any effect on anoxia. These results suggest that indeloxazine possesses anti-anoxic activities similar to calcium hopantenate. The mode of anti-anoxic actions of indeloxazine is also discussed.

Topics: Amitriptyline; Animals; Avoidance Learning; Cerebrovascular Circulation; Dihydroergotoxine; Female; gamma-Aminobutyric Acid; Hypoxia; Male; Mice; Mice, Inbred ICR; Morpholines; Pantothenic Acid; Piperazines; Rats; Rats, Inbred Strains; Sleep; Time Factors; Viloxazine

50 bastard dogs are anesthetized by chloralose (100 mg/kg) and mebubarbital (5 mg/kg) and then perfused by three-different dosages of dihydroergotoxine (DHET) (1.25; 2.5; 5 micrograms/kg/min). The effect of DHET on cerebral oxygenation is analyzed under two conditions: normoxia and hypercapnic hypoxia. The following biochemical and physiological parameters are studied: mean vertebral flow (MVF), aortic arterial pressure (AP), heart rate (HR); pO2, pCO2, total CO2, pH, haemoglobin saturation ratio, both in arteries and veins. Other parameters are calculated: O2 arterio-venous difference, CMRO2, O2 extraction coefficient, cerebral O2 supply, vertebral resistance. Under normoxia, DHET, whatever the dosage, induces a decrease of the MVF associated with an inconstant decrease of oxygen supply. At 2.5 micrograms/kg/min, a permanent and significant increase of CMRO2 is obtained. At 5 micrograms/kg/min, similar results are obtained although the decrease of HR and AP is more pronounced. Under hypoxia, the arterio-venous oxygen content difference and the CMRO2 are increased by DHET (2.5 micrograms/kg/min) without any repercussions on AP and MVF (hypothetical role of the blood pH decrease). In conclusion, DHET doubles the CMRO2, as a consequence of an increase of the oxygen extraction ratio. A 2.5 micrograms/kg/min dosage is by itself able to give this maximum effect without any major consequences on HR, AP and MVF. This effect is still obtained in hypoxia without any peripheral vascular effect.

Topics: Animals; Blood Pressure; Brain; Dihydroergotoxine; Dogs; Female; Hemodynamics; Hypercapnia; Hypoxia; Lung Diseases, Obstructive; Male; Oxygen; Oxygen Consumption; Respiration; Time Factors

An 18 h lasting moderate hypoxia equivalent to 7000 m altitude rises DOPAC level in the caudate nucleus and the mesolimbic area of the rat to about 130%. This elevation is counteracted by a singular high dose of nootropics of the "energy mobilizer" type, but not by vasoactive ones.

Topics: Animals; Brain; Caudate Nucleus; Diazepam; Dihydroergotoxine; Dopamine; Hypoxia; Meclofenoxate; Orotic Acid; Piracetam; Psychotropic Drugs; Pyrithioxin; Rats; Rats, Inbred Strains; Vinca Alkaloids

The synaptosomal fraction obtained from the motor area of the cerebral cortex of normocapnic, normoxic or hypoxic "young adult," "mature" and "senescent" beagle dogs is incubated and analyzed for : ATP, ADP, AMP, creatine phosphate, pyruvate and lactate. The data are compared with those obtained from the whole controlateral cortical motor area, by the surface freezing technique. After hypoxic hypoxia /15 min; PaO2 = 17-19 mm Hg), the metabolite contents and ratios are differently affected by ageing when the evaluations are performed in the incubated synaptosomal preparation or in the controlateral whole cerebral tissue. In fact, ageing does not affect so much the cerebral changes that occur in the overall energetic state during the hypoxic assault in vivo, but rather those that the synaptosomes remember the tend to reverse during the subsequent incubation in vitro. The protective action of several drugs on the synaptosomal phosphorylation state is tested. Phenobarbital shows a quite broad, age-independent spectrum of action. (-)Eburnamonine and dihydroergocristine exhibits a more limited, age-dependent effectiveness, but are devoid of anesthetic action. Papaverine proves unable to affect the tested biochemical parameters.

Topics: Adenine Nucleotides; Aging; Animals; Dihydroergotoxine; Dogs; Female; Hypoxia; Lactates; Lactic Acid; Motor Cortex; Phenobarbital; Phosphocreatine; Pyruvates; Pyruvic Acid; Synaptosomes; Vinca Alkaloids

A total of 800 physicians practising general medicine, internal medicine and neurology tested the dihydroergotoxin preparation Orphol Drops for a period of six weeks at a daily dose of 30 drops 3 times daily in 8940 patients with cerebrovascular insufficiency. The "cerebral symptom" complex showed the best results with improved findings in 94.5% of cases. The overall assessment of therapy by the doctors in the "psychological findings" complex showed improved findings in 85.7% of the patients affected after 6 weeks' treatment. The third complex, "harmonization of environmental relations" still showed improved findings in 71.6% of the affected patients. The sustained improvements in all three "complexes" were striking, also in the second period of the trial, which emphasizes the importance of longterm therapy of deficiency symptoms in cerebrovascular insufficiency.

Topics: Aged; Anxiety Disorders; Cerebrovascular Disorders; Cognition Disorders; Depression; Dihydroergotoxine; Drug Administration Schedule; Drug Tolerance; Headache; Humans; Hypoxia; Memory; Vertigo

Topics: Animals; Asphyxia; Dihydroergotoxine; Disease Models, Animal; Dose-Response Relationship, Drug; Hypoxia; Hypoxia, Brain; Mice; Rats

Topics: Adenosine Triphosphate; Animals; Brain Edema; Brain Ischemia; Cerebral Cortex; Cyanides; Dihydroergotoxine; Disease Models, Animal; Hypoxia; Indoles; Indoramin; Rats